CoChat
Sign Up
Cited by 144Cancer Cells and MetastasisCytokine Signaling Pathways and InteractionsCancer, Lipids, and Metabolism

Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells

Open access
Gyamfi, Jones, Lee, Yun-Hee, Eom, Minseob, Choi, Junjeong·2018·Scientific Reports
DOI 10.1038/s41598-018-27184-9PMC PMC5995871
Open this paper in CoChat — free accountOpen PDF

Abstract

The tumour microenvironment is a key regulators of tumour progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT). Induction of EMT is a key step for transition from a benign state to a metastatic tumour. Adipose tissue forms a bulk portion of the breast cancer microenvironment, emerging evidence indicates the potential for adipocytes to influence tumour progression through the secretion of adipokines that can induce EMT. The molecular mechanisms underlying how adipocytes enhance breast cancer progression is largely unknown. We hypothesized that paracrine signalling by adipocytes can activate EMT and results in increased migration and invasion characteristics of breast cancer cells. We found that IL-6 secreted by adipocytes induce EMT in breast cancer cells. The effect of IL-6 expression on EMT is mediated through activation of the signal transducer and activated of transcription 3 (STAT3). Blocking of IL-6 signalling in breast cancer cells and adipocytes, decreased proliferation, migration and invasion capabilities and altered the expression of genes regulating EMT. Together, our results suggest that matured human adipocytes can enhance the aggressive behaviour of breast cancer cells and induce an EMT-phenotype through paracrine IL-6/STAT3 signalling.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-018-27184-9

Cites

0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • IL-6 is a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6-STAT3 pathway.

    “IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [23]

    The Introduction and Discussion link IL-6 to breast cancer progression through STAT3 signalling, and the Results show reduced STAT3 activity when IL-6 signalling was blocked. The cited paper does not address autoimmunity or establish that IL-6 acts mainly through STAT3 across inflammation, autoimmunity and cancer; its findings are specific to adipocyte–breast cancer cell interactions. Page numbers are not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • IL-6-STAT3 signaling in adipocytes is involved in adipocyte-induced EMT in breast cancer cells and obesity-promoted HCC.

    “IL-6–STAT3 signaling in adipocytes is known to be involved in adipocyte-induced EMT in breast cancer cells (23) and obesity-promoted HCC (258).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [23]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 37

  1. [2]Mao Y Keller ET Garfield DH Shen K Wang J Stromal cells in tumor microenvironment and breast cancer Cancer metastasis reviews 2013 32 303 315 10.1007/s10555-012-9415-3 23114846 PMC4432936 · DOI · Paper page
  2. [3]Place AE Jin Huh S Polyak K The microenvironment in breast cancer progression: biology and implications for treatment Breast Cancer Res 2011 13 227 10.1186/bcr2912 22078026 PMC3326543 · DOI
  3. [4]Takebe, N., Warren, R. Q. & Ivy, S. P. Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 13, 211, doi: 210.1186/bcr2876 (2011). PMC3218933 21672282 · DOI
  4. [5]Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 14, 818–829, doi: 810.1016/j.devcel.2008.1005.1009 (2008). 18539112 · DOI
  5. [6]Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J Clin Invest. 119, 1420–1428, doi: 1410.1172/JCI39104 (2009). PMC2689101 19487818 · DOI · Paper page
  6. [7]Sullivan, N. J. et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 28, 2940–2947, doi: 2910.1038/onc.2009.2180, Epub2009 Jul 2946 (2009). PMC5576031 19581928 · DOI
  7. [9]Wang, Y. & Zhou, B. P. Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer. 30, 603–611, doi: 610.5732/cjc.5011.10226 (2011). PMC3702729 21880181 · DOI
  8. [10]Heldin, C. H., Landstrom, M. & Moustakas, A. Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol. 21, 166–176, doi: 110.1016/j.ceb.2009.1001.1021, Epub2009 Feb 1023 (2009). 19237272 · DOI
  9. [11]Moustakas, A. & Heldin, C. H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 98, 1512–1520, Epub 2007 Jul 1523 (2007). PMC11158989 17645776
  10. [12]D’Esposito, V. et al. Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5. Oncotarget. 7, 24495–24509, doi: 24410.18632/oncotarget.28336 (2016). PMC5029717 27027351 · DOI
  11. [13]Dirat, B. et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 71, 2455–2465, doi: 2410.1158/0008-5472.CAN-2410-3323 (2011). 21459803 · DOI
  12. [14]Carter, J. C. & Church, F. C. Mature breast adipocytes promote breast cancer cell motility. Exp Mol Pathol. 92, 312–317, doi: 310.1016/j.yexmp.2012.1003.1005. Epub 2012 Mar1015 (2012). 22445926 · DOI
  13. [15]Manabe Y Toda S Miyazaki K Sugihara H Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions J Pathol. 2003 201 221 228 10.1002/path.1430 14517839 · DOI
  14. [16]Tan J Buache E Chenard MP Dali-Youcef N Rio MC Adipocyte is a non-trivial, dynamic partner of breast cancer cells Int J Dev Biol 2011 55 851 859 10.1387/ijdb.113365jt 21948738 · DOI
  15. [17]Jiang, G. X. et al. Interleukin6 induces epithelialmesenchymal transition in human intrahepatic biliary epithelial cells. Mol Med Rep. 13, 1563–1569, doi: 1510.3892/mmr.2015.4706, Epub2015 Dec 1522 (2016). PMC4732846 26708270 · DOI
  16. [18]Johansson, J., Tabor, V., Wikell, A., Jalkanen, S. & Fuxe, J. TGF-beta1-Induced Epithelial-Mesenchymal Transition Promotes Monocyte/Macrophage Properties in Breast Cancer Cells. Front Oncol. 5:3., 10.3389/fonc.2015.00003. eCollection02015 (2015). PMC4306317 25674539 · DOI
  17. [19]Lv, Z. D. et al. Transforming growth factor-beta 1 enhances the invasiveness of breast cancer cells by inducing a Smad2-dependent epithelial-to-mesenchymal transition. Oncol Rep. 29, 219–225, doi: 210.3892/or.2012.2111. Epub2012 Oct 3830 (2013). 23129177 · DOI
  18. [20]Eichten, A. et al. Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade. Cancer Res. 76, 2327–2339, doi: 2310.1158/0008-5472.CAN-2315-1443. Epub2016 Feb 2326. (2016). 26921327 · DOI
  19. [21]Kim, S. Y. et al. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal. 25, 961–969. doi: 910.1016/j.cellsig.2013.1001.1007. Epub2013 Jan 1016 (2013). PMC3595341 23333246 · DOI
  20. [22]Middleton, K., Jones, J., Lwin, Z. & Coward, J. I. Interleukin-6: an angiogenic target in solid tumours. Crit Rev Oncol Hematol. 89, 129–139, doi: 110.1016/j.critrevonc.2013.1008.1004. Epub2013 Aug 1028 (2014). 24029605 · DOI
  21. [23]Xie G IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures Int J Oncol 2012 40 1171 1179 10.3892/ijo.2011.1275 22134360 PMC3584811 · DOI
  22. [24]Lee, Y., Jung, W. H. & Koo, J. S. Adipocytes can induce epithelial-mesenchymal transition in breast cancer cells. Breast Cancer Res Treat. 153, 323–335, doi: 310.1007/s10549-10015-13550-10549. Epub12015 Aug 10519 (2015). 26285644 · DOI
  23. [25]Yu, Y. et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer. 110, 724–732, doi: 710.1038/bjc.2013.1768. Epub2013 Dec 1012 (2014). PMC3915130 24335925 · DOI
  24. [26]Wang, C., Gao, C., Meng, K., Qiao, H. & Wang, Y. Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. PLoS One. 10, e0119348, doi: 0119310.0111371/journal.pone.0119348, eCollection0112015 (2015). PMC4352027 25747684 · DOI
  25. [27]Kushiro, K., Chu, R. A., Verma, A. & Nunez, N. P. Adipocytes Promote B16BL6 Melanoma Cell Invasion and the Epithelial-to-Mesenchymal Transition. Cancer Microenviron. 5, 73–82, 10.1007/s12307-12011-10087-12302 Epub12011 Sep 12303 (2012). PMC3343194 21892698 · DOI
  26. [28]Schaffler A Scholmerich J Buechler C Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer Nat Clin Pract Endocrinol Metab. 2007 3 345 354 10.1038/ncpendmet0456 17377617 · DOI
  27. [29]Vona-Davis, L. & Rose, D. P. Angiogenesis, adipokines and breast cancer. Cytokine Growth Factor Rev. 20, 193–201, doi: 110.1016/j.cytogfr.2009.1005.1007. Epub2009 Jun 1010 (2009). 19520599 · DOI
  28. [30]Soon, P. S. et al. Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr Relat Cancer. 20, 1–12, 10.1530/ERC-1512-0227. Print2013 Feb (2013). 23111755 · DOI
  29. [31]Wu, X. et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget. 8, 20741–20750, doi: 20710.18632/oncotarget.15119 (2017). PMC5400541 28186964 · DOI
  30. [32]Zhuang J TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT Sci Rep. 2015 5 11924 10.1038/srep11924 26152796 PMC4495469 · DOI
  31. [33]Bachelot T Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients Br J Cancer. 2003 88 1721 1726 10.1038/sj.bjc.6600956 12771987 PMC2377148 · DOI
  32. [34]Chung SS Giehl N Wu Y Vadgama JV STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Int J Oncol 2014 44 403 411 10.3892/ijo.2013.2195 24297508 PMC3898805 · DOI
  33. [35]Ye, X. et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 525, 256–260, doi: 210.1038/nature14897. Epub12015 Sep 14892 (2015). PMC4764075 26331542 · DOI
  34. [36]Zavadil J Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta Proc Natl Acad Sci USA 2001 98 6686 6691 10.1073/pnas.111614398 11390996 PMC34413 · DOI
  35. [37]Lee YH Petkova AP Mottillo EP Granneman JG In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding Cell Metab 2012 15 480 491 10.1016/j.cmet.2012.03.009 22482730 PMC3322390 · DOI
  36. [38]Liu, Z. Q., Mahmood, T. & Yang, P. C. Western blot: technique, theory and trouble shooting. N Am J Med Sci. 6, 160, doi: 110.4103/1947-2714.128482 (2014). PMC3978942 24741558 · DOI
  37. [39]Rosner, M. et al. Efficient siRNA-mediated prolonged gene silencing in human amniotic fluid stem cells. Nat Protoc. 5, 1081–1095, doi: 1010.1038/nprot.2010.1074. Epub2010 May 1020 (2010). 20539284 · DOI

Cited by

Sorted by citations

Authors
Gyamfi, J., Lee, Y.-H., Eom, M., & Choi, J.
Affiliations
Yonsei University (KR)
Corresponding author
Choi, Junjeong
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-06-11
Volume
8
Issue
1
Pages
8859-8859
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-27184-9
PMC
PMC5995871
OpenAlex
W2806229604
Cited by
144
References
0
Citations by year
2026: 6 · 2025: 17 · 2024: 14 · 2023: 20 · 2022: 22 · 2021: 24 · 2020: 23 · 2019: 13 · 2018: 5
FWCI
6.11
Type
journal article
Language
en
Update notices
correction (2020-07-29)
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation (2018R1A6A1A03023718)
  • Yonsei University
  • National Research Foundation of Korea (2018R1A6A1A03023718, NRF 2014R1A1A1002443, 2016M3C7A1913844)
  • Ministry of Education, Science and Technology (2018R1A6A1A03023718, 2017R1D1A1B03033362, 2014R1A1A1002443)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
interleukin-6, STAT3 signaling, epithelial-mesenchymal transition, breast cancer, adipocytes, tumor microenvironment, paracrine signaling, adipokines, cell migration, cell invasion, tumor progression, metastasis
MeSH terms
Breast Neoplasms, Cell Movement, Female, Humans, Neoplasm Invasiveness, Interleukin-6, Gene Expression Regulation, Neoplastic, Adipocytes, Paracrine Communication, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Epithelial-Mesenchymal Transition, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review